Hyperuricemia as a potential risk factor for type 2 diabetes and diabetic nephropathy

Serum uric acid has recently received attention as a potential biomarker independently predicting the development of hypertension, diabetes mellitus, and chronic kidney disease.^1-3 Elevated serum uric acid has also been reported to predict development of nephropathy in type 1 diabetes.^4-7 Less is known, however, about the role of serum uric acid in predicting nephropathy in type 2 diabetes.

In this issue of the Brazilian Journal of Nephrology, Fouad et al.⁸ performed a case-control study in Egyptian adults with and without type 2 diabetes that were matched for age, sex and body mass index (BMI). The study included 986 participants; 250 non-diabetic controls, 352 with type 2 diabetes for less than 5-years and 384 with type 2 diabetes for more than 5-years.

The participants of the three groups were similarly obese with mean BMI between 30 and 32 kg/m². The most important observation was that serum uric acid showed a stepwise increase between groups, and overall 32% of subjects with type 2 diabetes demonstrated hyperuricemia (defined as serum uric acid > 7.0 mg/dl). Furthermore, the increase in serum uric acid correlated with worsening hypertension, albuminuria and kidney function.

The paper is interesting for several reasons. First, some studies of diabetes mellitus have reported serum uric acid to be lower than what is observed in nondiabetic subjects, and this has been attributed to elevated GFR (hyperfiltration) and poor glycemic control (elevated HbA1c).^9,10 Bo et al.¹¹, however, noted that subjects with type 2 diabetes with kidney disease tended to have higher serum uric acid levels.

In the study by Fouad et al.⁸ the serum uric acid was higher in subjects with type 2 diabetes, with the highest levels of serum uric acid observed in those with poor glycemic control. One potential explanation provided by the authors was that their subjects already had kidney disease with falling eGFR, for which reason hyperfiltration that is commonly seen early in the course of diabetic kidney disease was not observed.

This may relate to the fact that in type 2 diabetes subjects often have other comorbidities including hypertension and/or vascular disease that may lead to earlier development of kidney disease than is normally observed during the initial years of type 1 diabetes. It is also possible that other risk factors may be playing an important role in causing early kidney disease in this population. One recently proposed risk factor is heat stress and dehydration, that may be more common among individuals living in hot environments.¹²

There are some limitations of the study worth mentioning. First, it is unclear if the elevated serum uric acid in subjects with type 2 diabetes simply reflects worse renal function among this group. It would have been interesting to determine if serum uric acid was elevated independently of the eGFR in subjects with type 2 diabetes.

Second, the study was cross-sectional, and hence it is not possible to determine causality, i.e. if elevated serum uric acid mediated the the development of nephropathy. Nevertheless, the observation that hyperuricemia was common in subjects with type 2 diabetes compared to non-diabetic control subjects with similar levels of obesity is fascinating, as is the stepwise increase in serum uric acid with duration of diabetes.

We have much more to learn about the role of uric acid in diabetes mellitus and diabetic kidney disease. Some early pilot studies suggest lowering serum uric acid can improve insulin resistance in subjects with heart failure or metabolic syndrome.^13,14 Other small studies suggest lowering serum uric acid may improve diabetic nephropathy.¹⁵

It is also interesting that the potential benefit of lowering serum uric acid may be primarily in subjects who are not taking agents that block the renin angiotensin system. For example, one Egyptian study reported marked exacerbation of nondiabetic kidney disease when serum uric acid lowering agents were withdrawn, but only in those not taking ACE inhibitors.¹⁶ Currently there is a large clinical trial ongoing in the North America to determine if lowering serum uric acid can halt or delay the development of nephropathy in subjects with type 1 diabetes.¹⁷

It would seem important to design a similar study in subjects with type 2 diabetes. In the meantime, given the potential toxicities of allopurinol, we do not recommend routine lowering of serum uric acid in patients with type 2 diabetes, but would reserve such treatment for those with gout, uric acid stones, or those with marked hyperuricemia (serum uric acid > 9.0 mg/dl).

References

• ¹
  Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2011;63:102-10. DOI: http://dx.doi.org/10.1002/acr.20344
  » http://dx.doi.org/10.1002/acr.20344
• ²
  Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol 2014;15:122. DOI: http://dx.doi.org/10.1186/1471-2369-15-122
  » http://dx.doi.org/10.1186/1471-2369-15-122
• ³
  Lv Q, Meng XF, He FF, Chen S, Su H, Xiong J, et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLoS One 2013;8:e56864. DOI: http://dx.doi.org/10.1371/journal.pone.0056864
  » http://dx.doi.org/10.1371/journal.pone.0056864
• ⁴
  Ficociello LH, Rosolowsky ET, Niewczas MA, Maselli NJ, Weinberg JM, Aschengrau A, et al. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care 2010;33:1337-43. DOI: http://dx.doi.org/10.2337/dc10-0227
  » http://dx.doi.org/10.2337/dc10-0227
• ⁵
  Jalal DI, Rivard CJ, Johnson RJ, Maahs DM, McFann K, Rewers M, et al. Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant 2010;25:1865-9. DOI: http://dx.doi.org/10.1093/ndt/gfp740
  » http://dx.doi.org/10.1093/ndt/gfp740
• ⁶
  Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes 2009;58:1668-71. DOI: http://dx.doi.org/10.2337/db09-0014
  » http://dx.doi.org/10.2337/db09-0014
• ⁷
  Bjornstad P, Roncal C, Milagres T, Pyle L, Lanaspa MA, Bishop FK, et al. Hyperfiltration and uricosuria in adolescents with type 1 diabetes. Pediatr Nephrol 2016;31:787-93. DOI: http://dx.doi.org/10.1007/s00467-015-3299-8
  » http://dx.doi.org/10.1007/s00467-015-3299-8
• ⁸
  Fouad M. Serum uric acid and its association with hypertension, early nephropathy and chronic kidney disease in type 2 diabetic patients. J Bras Nefrol 2016;38:403-10
• ⁹
  Lytvyn Y, Škrtić M, Yang GK, Yip PM, Perkins BA, Cherney DZ. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol 2015;308:F77-83. DOI: http://dx.doi.org/10.1152/ajprenal.00555.2014
  » http://dx.doi.org/10.1152/ajprenal.00555.2014
• ¹⁰
  Bjornstad P, Paul Wadwa R, Sirota JC, Snell-Bergeon JK, McFann K, Rewers M, et al. Serum uric acid and hypertension in adults: a paradoxical relationship in type 1 diabetes. J Clinl Hypertens (Greenwich) 2014;16:283-8. DOI: http://dx.doi.org/10.1111/jch.12305
  » http://dx.doi.org/10.1111/jch.12305
• ¹¹
  Bo S, Cavallo-Perin P, Gentile L, Repetti E, Pagano G. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest 2001;31:318-21. DOI: http://dx.doi.org/10.1046/j.1365-2362.2001.00812.x
  » http://dx.doi.org/10.1046/j.1365-2362.2001.00812.x
• ¹²
  Glaser J, Lemery J, Rajagopalan B, Diaz HF, García-Trabanino R, Taduri G, et al. Climate Change and the Emergent Epidemic of CKD from Heat Stress in Rural Communities: The Case for Heat Stress Nephropathy. Clin J Am Soc Nephrol 2016;11:1472-83. DOI: http://dx.doi.org/10.2215/CJN.13841215
  » http://dx.doi.org/10.2215/CJN.13841215
• ¹³
  Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010;3:73-81. DOI: http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.868604
  » http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.868604
• ¹⁴
  Takir M, Kostek O, Ozkok A, Elcioglu OC, Bakan A, Erek A, et al. Lowering Uric Acid With Allopurinol Improves Insulin Resistance and Systemic Inflammation in Asymptomatic Hyperuricemia. J Investig Med 2015;63:924-9. DOI: http://dx.doi.org/10.1097/JIM.0000000000000242
  » http://dx.doi.org/10.1097/JIM.0000000000000242
• ¹⁵
  Momeni A, Shahidi S, Seirafian S, Taheri S, Kheiri S. Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients. Iran J Kidney Dis 2010;4:128-32.
• ¹⁶
  Talaat KM, el-Sheikh AR. The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am J Nephrol 2007;27:435-40. DOI: http://dx.doi.org/10.1159/000105142
  » http://dx.doi.org/10.1159/000105142
• ¹⁷
  Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, et al.; PERL Consortium. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep 2013;13:550-9. DOI: http://dx.doi.org/10.1007/s11892-013-0381-0
  » http://dx.doi.org/10.1007/s11892-013-0381-0

Publication Dates

• Publication in this collection
  Oct-Dec 2016

History

• Received
  09 June 2016
• Accepted
  09 Oct 2016